The mammalian ovary is unique in that its reproductive lifespan is limited by oocyte quantity and quality. Oocytes are recruited from a finite pool of primordial follicles that are usually exhausted from the ovary during mid-adult life. If regulation of this pool is perturbed, the reproductive capacity of the ovary is compromised. Previous characterization of TAF4b-deficient mouse ovaries revealed several reproductive deficits that collectively result in female infertility. By assessing estrous cyclicity, ovarian pathology and gene expression changes in young TAF4b-deficient female mice, we have determined that TAF4b-null females exhibit premature reproductive senescence. Based on these preliminary data, we hypothesize that TAF4b regulates the transcription of oocyte-specific genes required for proper maintenance of the primordial follicle pool and oocyte quality that is required for healthy fertility in the adult. The objective of the proposed research is to decipher fundamental cellular and molecular mechanisms of TAF4b in the regulation of proper primordial follicle survival and ovarian aging. To accomplish our goals we propose three related, but non-overlapping specific aims to: 1) determine the cellular mechanisms of excessive neonatal TAF4b-deficient primordial follicle attrition; 2) elucidate the TAF4b regulation of chromosome synapsis, segregation and meiosis; and 3) determine the mechanistic basis of TAF4b-dependent regulation of oocyte quality. Since TAF4b is required for normal regulation of primordial follicle development in the mouse, deregulation of TAF4b-mediated events in human ovaries may be an underlying cause of a number of female fertility defects including unexplained infertility, which accounts for 10% of female infertility, and premature ovarian failure, which is observed in 1% of the female population worldwide. In fact, recent studies of human fertility have implicated the sequence of the human TAF4b gene and its proper expression as being critical for promoting healthy oocyte quality and ovarian aging in women. Thus, elucidating the critical cellular and molecular mechanisms of TAF4b in postnatal oocyte developmental will both identify fundamental biological principles of mammalian ovarian biology as well as illuminate the etiology of female reproductive health disorders in women such as primary ovarian insufficiency. These studies will increase our basic knowledge which may allow us to preserve and/or enhance oocyte quality in women of future generations. PUBLIC HEALTH RELEVANCE: Primary ovarian insufficiency (POI), also referred to as premature ovarian failure, affects approximately 1% of women worldwide. Our preliminary data implicate TAF4b-regulated processes in the expression of critical genes in the ovary that are required for the maintenance of the primordial follicle pool and healthy ovarian aging. As recent studies of human fertility have independently linked TAF4b functions to proper ovarian aging and oocyte quality, the work proposed here to uncover the mechanisms of TAF4b in regulating ovarian aging will reveal fundamental biological principles underlying reproductive functions in women that are required for healthy fertility. These studies may lead to advanced diagnostic and therapeutic tools to better address and manage female infertility.